Structural Basis for the Function of the C-Terminal Proton Release Pathway in the Calcium Pump

The calcium pump (sarco/endoplasmic reticulum Ca²⁺-ATPase, SERCA) plays a major role in calcium homeostasis in muscle cells by clearing cytosolic Ca²⁺ during muscle relaxation. Active Ca²⁺ transport by SERCA involves the structural transition from a low-Ca²⁺ affinity E2 state toward a high-Ca²⁺ affinity E1 state of the pump. This structural transition is accompanied by the countertransport of protons to stabilize the negative charge and maintain the structural integrity of the transport sites and partially compensate for the positive charges of the two Ca²⁺ ions passing through the membrane. X-ray crystallography studies have suggested that a hydrated pore located at the C-terminal domain of SERCA serves as a conduit for proton countertransport, but the existence and function of this pathway have not yet been fully characterized. We used atomistic simulations to demonstrate that in the protonated E2 state and the absence of initially bound water molecules, the C-terminal pore becomes hydrated in the nanosecond timescale. Hydration of the C-terminal pore is accompanied by the formation of water wires that connect the transport sites with the cytosol. Water wires are known as ubiquitous proton-transport devices in biological systems, thus supporting the notion that the C-terminal domain serves as a conduit for proton release. Additional simulations showed that the release of a single proton from the transport sites induces bending of transmembrane helix M5 and the interaction between residues Arg762 and Ser915. These structural changes create a physical barrier against full hydration of the pore and prevent the formation of hydrogen-bonded water wires once proton transport has occurred through this pore. Together, these findings support the notion that the C-terminal proton release pathway is a functional element of SERCA and also provide a mechanistic model for its operation in the catalytic cycle of the pump.     

Computational Investigation Identified Potential Chemical Scaffolds for Heparanase as Anticancer Therapeutics

Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer.     

Prediction of Chameleonic Efficiency

Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Ų was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R²=0.92) with an experimental measure of hydrogen bond donor potential, Δlog P_oct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility.     

珠江口盆地珠一坳陷古近系高自然伽马砂岩形成机制及油气地质意义

运用放射性元素寻找油气是一种非常规油气勘探手段。近年来,在珠江口盆地珠一坳陷富烃凹陷周边古近系钻遇高自然伽马(GR)砂岩,其GR值(100~300 API)甚至大于同区泥岩的GR值(100~200 API)。为了弄清该特殊现象背后的地质意义,对珠江口盆地珠一坳陷古近系高自然伽马砂岩开展了铀(U)、钍(Th)、钾(K)等3种元素含量与GR值的相关趋势线分析,从井震特征、岩性特征及矿物成分特征等入手分析了砂岩GR值增高的主要原因及成因机制,探讨了放射性元素聚集的条件、运移通道、驱动力以及油气意义。结果表明:西江、惠州地区由U含量增高导致砂岩GR值偏高,恩平、番禺地区由K,Th含量增高导致砂岩GR值偏高;砂岩GR值增高有两大成因机制,一是地下流体带来的放射性元素离子U4+在氧化-还原面处富集后导致地层GR值偏高,这种特殊现象说明在具有连通基底大断裂旁的圈闭中,U4+的富集指示了曾经油气的存在,证实了研究区油气运移通道的有效性,对于油气藏的预测有着非常重要的指导性意义,二是地表流体带来的含放射性元素的矿物大量沉积后导致地层GR值偏高,含放射性元素矿物性质不稳定,可指示近源供给的存在,对于判断物源及沉积环境有着非常重要的意义。该研究成果为预测研究区油气成藏有利区带提供了依据。     

Xanthohumol for Human Malignancies: Chemistry,Pharmacokinetics and Molecular Targets

Xanthohumol (XH) is an important prenylated flavonoid that is found within the inflorescence of Humulus lupulus L. (Hop plant). XH is an important ingredient in beer and is considered a significant bioactive agent due to its diverse medicinal applications, which include anti-inflammatory, antimicrobial, antioxidant, immunomodulatory, antiviral, antifungal, antigenotoxic, antiangiogenic, and antimalarial effects as well as strong anticancer activity towards various types of cancer cells. XH acts as a wide ranging chemopreventive and anticancer agent, and its isomer, 8-prenylnaringenin, is a phytoestrogen with strong estrogenic activity. The present review focuses on the bioactivity of XH on various types of cancers and its pharmacokinetics. In this paper, we first highlight, in brief, the history and use of hops and then the chemistry and structure–activity relationship of XH. Lastly, we focus on its prominent effects and mechanisms of action on various cancers and its possible use in cancer prevention and treatment. Considering the limited number of available reviews on this subject, our goal is to provide a complete and detailed understanding of the anticancer effects of XH against different cancers.     

Osteosarcoma Pathogenesis Leads the Way to New Target Treatments

Osteosarcoma (OS) is a rare condition with very poor prognosis in a metastatic setting. Basic research has enabled a better understanding of OS pathogenesis and the discovery of new potential therapeutic targets. Phase I and II clinical trials are already ongoing, with some promising results for these patients. This article reviews OS pathogenesis and new potential therapeutic targets.     

基于纸喷雾离子化衍生质谱法快速检测PM2.5中的醌污染物

醌类化合物是PM2.5中的一类有害物质。本研究建立了纸喷雾离子化衍生质谱法快速测定PM2.5中的醌类污染物。通过衍生化反应在醌化合物中引入氨基，提高醌在纸喷雾中的离子化效率。随后对衍生化试剂种类、电压、喷雾溶剂种类等反应条件进行优化。在最优实验条件下，采用内标法定量分析1,4-苯醌、甲基对苯醌、1,4-萘醌和1,4-蒽醌，4种化合物均呈现较好的线性关系，其检出限分别为4.49、20.89、0.13、0.17 ng。利用该方法分析PM2.5实际样品中的萘醌和蒽醌，均获得了较好的定性和定量结果。     

Thermal prehistory,structure and high-temperature thermodynamic properties of Y2O3-CeO2 and Y2O3-ZrO2-CeO2 solid solutions

Ceria-based solid solutions are important materials for high- and medium-temperature electrochemical applications. However, the stabilities of both binary and ternary ceria-based solid solutions are insufficient at elevated temperatures, which limits their application as solid electrolytes or SOFC cathodes. Data on the high-temperature stability of ceria-based ceramics are unavailable in the literature. In the present study, we report a thermodynamic stability investigation of Y₂O₃-CeO₂ and Y₂O₃-ZrO₂-CeO₂ solid solutions. The thermal prehistories of binary and ternary systems were investigated using STA, XRD, and ESCA techniques. The vaporization processes were investigated in the temperature range of 1577–2227°С via the Knudsen effusion mass spectrometry technique. Using data on the component activity in solid-phase thermodynamic properties of Y₂O₃-CeO₂ solid solutions, which is represented as the Gibbs energy, the excess Gibbs energy was calculated as a function of the ceria mol. %. It was shown that the reduction of Ce⁴⁺ to Ce³⁺ in Y₂O₃-CeO₂ and Y₂O₃-ZrO₂-CeO₂ solid solutions corresponds to less-negative Gibbs energy compared to ZrO₂-CeO₂ solid solutions.     

Free energy of conformational change in a single chain of polyvinylidene fluoride using molecular simulations

Polyvinylidene fluoride (PVDF) has several crystal forms of which the α-form is nonpolar, while the β-form is polar and has the highest piezoelectric constant. α PVDF, when stretched, transforms into the β form, which has wide applications in sensors and actuators. Steered molecular dynamics simulations are used to study the transformation of a single chain of PVDF from a trans–gauche conformation to an all trans one. The Helmholtz free energy change (∆F) is estimated using Jarzynski's equality. The transformation starts at the chain ends followed by the transformation of the remaining chain. The free energy change for the transformation is found to be always positive, indicating that the TGTG' form has higher thermodynamic stability than the all trans form throughout the studied temperature range. With increasing temperature, free energy change for the transformation increases monotonically.     

Surface modification of cellulose nanocrystals towards new materials development

Cellulose nanocrystals (CNCs) are a kind of sustainable nanoparticle from biomass, which are widely used as reinforcing filler and assembly building block for high-performance composites and function materials including biomaterial, optics, and so forth. Here, their unique advantages in material applications were reviewed based on their rod-like morphology, crystalline structure, dimension-related effects, and multi-level order structure. Then, we focused on the molecular engineering of CNCs, including the structure and physicochemical properties of their surface, along with surface modification methods and steric effects. We further discussed the performance-improvement and functionalization methods based on multi-component complex systems, together with the effects of surface molecular engineering on the performance and functions. Meanwhile, methods of optimizing orientation in uniaxial arrays were discussed along with those of enhancing photoluminescence efficiency via surface chemical modification and substance coordination. In the end, we prospected the design, development, and construction methods of new CNCs materials.